Quantification of Scheduling Impact on Safety and Efficacy Outcomes of Brain Metastasis Radio- and Immuno-Therapies: A Systematic Review and Meta-Analysis

Abstract

Objectives: The goal of this quantitative research was to evaluate the impact of various factors (e.g., scheduling or radiotherapy (RT) type) on outcomes for RT vs. RT in combination with immune checkpoint inhibitors (ICI), in the treatment of brain metastases, via a meta-analysis. Methods: Clinical studies with at least one ICI+RT treatment combination arm with brain metastasis patients were identified via a systematic literature search. Data on 1-year overall survival (OS), 1-year local control (LC) and radionecrosis rate (RNR) were extracted; for combination studies which included an RT monotherapy arm, odds ratios (OR) for the aforementioned endpoints were additionally calculated and analyzed. Mixed-effects meta-analysis models were tested to evaluate impact on outcome, for different factors such as combination treatment scheduling and the type of ICI or RT used. Results: 40 studies representing a total of 4,359 patients were identified. Higher 1-year OS was observed in ICI and RT combination vs. RT alone, with corresponding incidence rates of 59% [95% CI: 54-63%] vs. 32% [95% CI: 25-39%] ( P < 0.001). Concurrent ICI and RT treatment was associated with significantly higher 1-year OS vs. sequential combinations: 68% [95% CI: 60-75%] vs. 54% [95% CI: 47-61%]. No statistically significant differences were observed in 1-year LC and RNR, when comparing combinations vs. RT monotherapies, with 1-year LC rates of 68% [95% CI: 40-90%] vs. 72% [95% CI: 63-80%] ( P = 0.73) and RNR rates of 6% [95% CI: 2-13%] vs. 9% [95% CI: 5-14%] ( P = 0.37). Conclusions: A comprehensive, study-level meta-analysis of brain metastasis disease treatments suggest that combinations of RT and ICI result in higher OS, yet comparable neurotoxicity profiles vs. RT alone, with a superiority of concurrent vs. sequential combination regimens. A similar meta-analysis using patient-level data from past trials, as well as future prospective randomized trials would help confirming these findings.

Combination of the EP and Anti-PD-1 Pathway or Anti-CTLA-4 for the Phase III Trial of Small-Cell Lung Cancer: A Meta-Analysis

“…Moreover, most of the patients with brain metastasis need dexamethasone treatment. ere is no advantage of CPIs for PFS and OS in the existence of brain and liver metastasis [31,32]. e limitation of this study is that it only included 4 RCTs, which could be considered a small number.…”

“…All four studies included patients with brain metastasis. e brain and liver metastasis are worth mentioning at the beginning of treatment because of their correlation with poor prognosis [31]. e microenvironment of the brain and liver might not be suitable for CPIs in SCLC.…”

Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

“…Concurrent ICI (within two weeks) was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted a decreased likelihood of developing ≥ 3 new BMs after SRS [198]. A comprehensive, study-level meta-analysis of BM treatments suggests that combinations of RT and ICI result in higher OS, yet comparable neurotoxicity profiles vs. RT alone, with the superiority of concurrent vs. sequential combination regimens [197].…”

“…While there are several ongoing clinical trials that aim to compare the efficacy of ICIs in combination with either WBRT or SRS, there are only a few trials that are specifically designed to evaluate how different schedules affect the safety and efficacy of combined treatment [27]. The optimal schedule is tumor-type and immunotherapy-dependent [27]; however, to date, majority of trials report data that provide evidence for the benefit of concurrent schedules [186,[196][197][198][199] and the lowest response rate if radiotherapy is administered after immunotherapy [27]. Concurrent ICI (within two weeks) was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted a decreased likelihood of developing ≥ 3 new BMs after SRS [198].…”

Oncologic Outcome and Immune Responses of Radiotherapy with Anti-PD-1 Treatment for Brain Metastases Regarding Timing and Benefiting Subgroups

“…Literature regarding the increased risk of adverse radiation effects such as radionecrosis in patients treated concurrently with RT-ICI, especially SRS, is inconsistent, including meta-analyses and reviews indicating that the risk of adverse effects is not increased [ 39 , 62 , 63 ]. Overall, radionecrosis rates of 0–37% are reported after SRS.…”